The present invention relates to compounds and methods for producing compounds that are useful as photoselective compounds in photodynamic therapy. Specifically, the invention is directed to solid forms of tin ethyl etiopurpurin and their production and isolation.
Tin ethyl etiopurpurin, which has the name (OC-6-13) Dichloro[rel-ethyl (18R, 19S)-3,4,20,21-tetradehydro-4,9,14,19-tetraethyl-18,19-dihydro-3,8,13,18-tetramethyl-20-phorbinecarboxalato(2-)-xcexaN23, xcexaN24, xcexaN25, xcexaN26]tin, or xe2x80x9cSnET2xe2x80x9d, has the following structure. 
SnET2 as described and claimed in U.S. Pat. No. 5,051,415 (Sep. 24, 1991) shows potent pharmacological activity when irradiated with light and may be used in photodynamic therapy for the treatment and diagnosis of a range of diseases.
The solid forms of SnET2 are particularly important because they enable SnET2 to be conveniently manufactured, purified, transported and formulated in, for example, tablets or capsules or any other type of dosage form such as lozenges or rapidly dissolving tablets for oral administration, suspensions for oral administration, or other formulation such as suppositories, or topical formulations, or dissolved in suitable solvents as a solution or any other formulation for parenteral or topical administration.
However, the present inventors are not aware of any work by others to produce, isolate, or characterize solid forms of SnET2.
Accordingly, there is a need to produce SnET2 in a pure and highly crystalline form to fulfill exacting pharmaceutical requirements and specifications and to meet regulatory requirements for approval and marketing.
The crystalline forms of SnET2 are of particular interest since they are more stable than the amorphous forms. There may, however, also be advantages to producing SnET2 in an amorphous solid form to achieve the solubility advantages of this form.
There is also a need for a process for producing SnET2 that is convenient to operate on a plant scale. In particular, it is desirable that the solid forms of SnET2 be prepared with convenient solvents and that the solvents be readily recoverable.
In addition, the product should be in a form that is readily filtered off and easily dried. It also is desirable that the product can be recrystallized from the same solvent system used to prepare the original form.
The present inventors have produced and isolated SnET2 in two crystalline forms designated crystalline Form I and crystalline Form II, and in an amorphous form. The crystalline forms can be prepared by, for example, crystallization or slurrying in various solvents. These forms have the desirable feature of being easily filterable and dried and have advantageous properties with respect to the manufacturing process. In addition, they have consistent X-ray diffraction patterns which provides a convenient means of control. Furthermore, crystalline Form II is more stable than crystalline Form I and crystalline Form I can be converted to both crystalline and disordered Form II by, for example, slurrying in dichloromethane, acetone, and mixtures. The amorphous form can be prepared, for example, by grinding either of the crystalline forms.
In addition, the process by which SnET2 is produced often yields a disordered form of crystalline Form II, hereinafter referred to as disordered Form II. This form has the desirable feature of being easily filterable and dried and has advantageous properties with respect to the manufacturing process. It also has a consistent X-ray diffraction pattern which provides a convenient means of control. As used herein in the specification and claims, the term xe2x80x9cForm IIxe2x80x9d refers to both crystalline Form II and disordered Form II.
SnET2 may also be obtained in two solvates (1,2-dichloroethane and dimethylformamide). These forms have the desirable feature of being easily filterable and dried and have advantageous properties with respect to the manufacturing process. In addition, they have consistent X-ray diffraction patterns which provides a convenient means of control.
Additional advantages of the invention will be set forth in the detailed description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention can be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.